This proposed research concerns the identification and the study of hereditary metabolic disorders of aminoacids, organic acids and related compounds in the human, particularly those causing mental retardation and other neurological and metabolic abnormalities. The specific diseases to be studied include hyperornithinemic syndromes (gyrate atrophy of the choroid and retina due to ornithine ketoacid transaminase deficiency, the syndrome of hyperornithinemia, hyperammonemia and homocitrullinuria, and hyperornithinemia with mental retardation and liver disease), disorders of sulfur aminoacid metabolism (sulfite oxidase deficiency, beta-mercaptolactate cystein disulfiduria, and an unidentified disulfiduria associated with mental retardation), hyperphenylalanimenia due to dihydropteridine reductase deficiency, maternal phenylketonuria, and non-ketototic hyperglycinemia. Various studies in these metabolic diseases have been proposed: 1) genetic complementation analysis in heterokaryons derived from mutant fibroblasts to study the genetic basis of biochemical heterogeneity; 2) delineation of enzyme defects and identification of unknown metabolites; 3) investigation of pathogenesis of neurological dysfunction, particularly the role of GABA and glycine by in vitro and in vivo experiments; 4) development of procedures for neonatal and prenatal diagnosis; 5) analysis of the relation of maternal biochemical defects to offspring abnormality; 6) evaluation of the biochemical and clinical effect of dietary therapy.